Anti-glomerular Basement Membrane Disease

Dr Stephen P. McAdoo & Prof Charles D. Pusey

Centre for Inflammatory Disease, Department of Medicine, Imperial College London

Corresponding Author: Stephen P. McAdoo, Centre for Inflammatory Disease, Department

of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road,

London W12 0NN; e-mail: s.mcadoo@imperial.ac.uk; telephone: +44 208 383 3152; fax:

+44 208 383 2062.

Word Count: 3965

Abstract: 210

Tables: 4

Figures: 2

References: 99

Running Title: Anti-GBM disease

Abstract

Anti-glomerular basement membrane disease is a rare but life-threatening autoimmune

vasculitis that is characterised by the development of pathogenic autoantibodies to type IV

collagen antigens expressed in the glomerular and alveolar basement membranes. Once

deposited in tissue, these autoantibodies incite a local capillarititis which manifests as rapidly

progressive glomerulonephritis in 80-90% of patients, and with concurrent alveolar

haemorrhage in approximately 50%. A small proportion of cases present with pulmonary

disease in isolation. Serological testing for anti-GBM antibodies may facilitate rapid

diagnosis, though renal biopsy is often required to confirm the presence of necrotizing or

crescentic glomerulonephritis and linear deposition of autoantibody on the glomerular

basement membrane. Alveolar haemorrhage may be evident clinically, or detected on

imaging, pulmonary function testing, or bronchoscopy. Prompt treatment with

plasmapheresis, cyclophosphamide and steroids is usually indicated to remove pathogenic

autoantibodies, to prevent their ongoing production, and to ameliorate end-organ

inflammation. Alveolar haemorrhage is usually responsive to this treatment, and long-term

respiratory sequalae are uncommon. Renal prognosis is more variable, though with

aggressive treatment, independent renal function is maintained at one year in over 80% of

patients not requiring renal replacement therapy at presentation. Relapse in uncommon in

anti-GBM disease, unless there is a concomitant anti-neutrophil cytoplasm antibody (present

in 30-40%), in which case maintenance immunosuppression is recommended.

Keywords:

Rapidly progressive glomerulonephritis; alveolar haemorrhage; pulmonary-renal syndrome;

plasmapheresis; anti-neutrophil cytoplasm antibody; Goodpasture syndrome.

Anti-glomerular basement membrane (anti-GBM) disease is a rare, life-threatening small

vessel vasculitis that can affect both glomerular and alveolar capillaries, resulting in rapidly

progressive glomerulonephritis (RPGN) and diffuse alveolar haemorrhage. It is typified by

the presence of autoantibodies directed against antigens intrinsic to the basement membranes

of both the kidney and the lung, which can be detected in serum or deposited in tissue. These

antibodies have been shown to be directly pathogenic, thus it is often considered a prototypic

model of autoantibody-mediated disease. Indeed, the first comprehensive clinical description

was of ‘anti-glomerular basement membrane antibody-induced glomerulonephritis’ in 19731,

and its recent addition to the Revised Chapel Hill Consensus Conference Nomenclature of

Vasculitides in 2012 retains the terminology ‘anti-glomerular basement membrane disease’,

though qualifies the misnomer given the involvement of alveolar basement membranes in

many cases2. It is still sometimes referred to as Goodpasture disease, an eponymous label first

employed in the 1950s3, in a report itself referring to a prior case in 19194. Goodpasture

syndrome may be used, less specifically, to refer to any pulmonary-renal presentation,

whereas Goodpasture disease is generally reserved for those with demonstrable anti-GBM

autoantibodies.

Epidemiology

Anti-GBM disease is rare, with an incidence to 1-2/million/year in European populations5. It

is also well recognised in Asian populations, but thought to be less common in those of

African descent. Larger series describe a bimodal age distribution, with peak incidence in the

third and seventh decade6,7. Both male and female patients are affected, though there is

preponderance for male patients in those presenting in early adulthood, and slight female

preponderance in those presenting in later life. In renal biopsy series, it accounts for

approximately 15% of cases of crescentic glomerulonephritis8, though it is a rare cause of

end-stage renal disease (ESRD) in both adults and children9,10. Single-centre series suggest

that 15-20% of pulmonary-renal syndromes are caused by anti-GBM disease11-13.

Pathogenesis

The accepted paradigm of autoimmune disease pathogenesis proposes that an environmental

insult to a genetically susceptible individual results in miscommunication between the innate

and adaptive immune systems, breakdown of tolerance, and the recognition of self-antigens

as the target of a damaging immunologic response14. The principle target of the autoimmune

response in anti-GBM disease is the non-collagenous domain of the alpha-3 chain of type IV

collagen, α3(IV)NC1, and though there is increasing understanding of the genetic and

environmental factors that contribute to disease, the precise molecular mechanisms of disease

induction are not fully understood.

Genetics

Anti-GBM disease has strong positive and negative HLA-associations. Inheritance of HLA-

DR15 is consistently associated with disease susceptibility in Caucasian and Asian

populations, whereas HLR-DR1, -DR7 and –DR9 are negatively associated with disease

risk15-17. Indeed, HLA-DR1 and -DR7 appear to confer a ‘dominant’ negative protective affect

if co-inherited with HLA-DR15. A recent series of studies using mice transgenic for human

HLA molecules (and lacking murine MHC Class II) confirms these epidemiologic

observations: HLA-DR15 transgenic mice are susceptible to induction of experimental anti-

GBM disease, whereas mice transgenic for either HLA-DR1 or both HLA-DR15 and DR1

are resistant18,19. These studies suggest that presentation of the immunodominant T cell

epitope in the distinct binding registries of HLA-DR15 and –DR1 can differentially induce

conventional and tolerogenic T cell responses, respectively, thus accounting for the dominant

protective effect of HLA-DR1 via induction of antigen-specific regulatory T cells, even when

co-inherited with the HLA-DR15 susceptibility allele.

In contrast to other antibody associated glomerular diseases, such as ANCA-associated

vasculitis and membranous nephropathy, where genome-wide association studies have

identified polymorphisms in the target autoantigen associated with disease susceptibility, a

small study did not identify any polymorphisms in COL4A3, the gene encoding the anti-

GBM disease autoantigen, related to disease predisposition20.

Environment

Historical series describe seasonal variation and anecdotal ‘outbreaks’ of anti-GBM

disease6,21, and a recent nationwide study in Ireland used formal statistical modelling to

identify both spatial and temporal clustering of cases5, suggesting that environmental triggers

may contribute to disease pathogenesis. Influenza infection has been implicated in some of

these clusters22,23, and a recent Chinese study identified a high proportion of patients with

prodromal respiratory tract infection at the time of anti-GBM disease diagnosis24. A number

of mechanisms may account for this association with infection, such as the release of usually

sequestered basement-membrane antigens as a result of pulmonary infection, or through

bystander activation of autoreactive T and B lymphocytes in the milieu of systemic

inflammation. Studies in experimental animal models have also suggested that autoimmunity

to basement membrane antigens may arise though a process of ‘molecular mimicry’ or

idiotype anti-idiotype interactions following a primary response to microbial or other foreign

peptides25,26. Excess reactivity to microbial peptides has been described in patients with anti-

GBM disease27, though causality has not been established in humans.

Exposure to pulmonary irritants is associated with the development of lung haemorrhage in

anti-GBM disease, which occurs in nearly all patients who smoke but less frequently in non-

smokers28. Hydrocarbon exposure has likewise been implicated in disease onset29,30, and there

are case reports of anti-GBM disease after use of inhaled recreational drugs including cocaine

and amphetamine31-33. It has been suggested that pulmonary irritants may increase capillary

permeability, thus predisposing to alveolar bleeding, or that they may modify or expose

sequestered basement membrane antigens to immune detection, resulting in disease

enhancement.

Exposure to the drug alemtuzumab, a lymphocyte-depleting monoclonal anti-CD52 mAb

used in the treatment of multiple sclerosis, has recently been implicated in developing anti-

GBM disease (and other autoimmune phenomena)34,35. It has been proposed that T cell

reconstitution after alemtuzumab is driven largely by homeostatic expansion of cells that

have escaped deletion (rather than by thymopoesis), resulting in a T cell pool that is enriched

for autoreactive cells and predisposition to clinical autoimmunity36.

Autoimmunity

The principle target of the autoimmune response in anti-GBM disease is the non-collagenous

domain of the alpha-3 chain of type IV collagen, α3(IV)NC137,38. The collagen IV family

consists of six genetically distinct α-chains (α1-6) that trimerize with each other to make

specific triple-helical protomers - α1α1α2, α3α4α5, and α5α5α6 – that then polymerise to

form the collagen IV network. The expression of the α3α4α5 protomer is restricted to the

glomerular and alveolar basement membranes (with the α1α1α2 protomer being most

abundantly expressed elsewhere), thus accounting for the clinical presentation of pulmonary-

renal syndrome in anti-GBM disease.

Compelling evidence for the direct pathogenicity of anti-GBM antibodies was provided by

adoptive transfer experiments, wherein immunoglobulins eluted from kidneys taken from

humans with anti-GBM disease were administered to non-human primates, resulting in the

development of glomerulonephritis in recipients39. The pathogenicity of anti-GBM antibodies

has since been replicated in a number of species and experimental models. In clinical studies,

antibody concentration and affinity correlate with the severity of renal disease at

presentation40-43. Antibody subclass has also been associated with disease severity, with an

increased proportion of IgG1 and IgG3 autoantibody in patients with more severe disease44,45.

Treatment to rapidly remove circulating antibodies with plasmapheresis is associated with

improved clinical outcomes in anti-GBM disease46, and if renal transplantation is performed

in the presence of detectable antibody, disease may recur immediately in the graft1,47.

All patients have autoantibodies reactive to α3(IV)NC1, and a proportion also show reactivity

to α5(IV)NC1 and α4(IV)NC1, demonstrated upon antibody elution from diseased kidney

tissue48. It has been suggested that reactivity to other collagen chains arises after a primary

response to α3(IV)NC1 via a process of inter-molecular epitope spreading. Circulating anti-

α1(IV)NC1 antibodies have also been described, and associated with the development of

pulmonary involvement49.

While anti-GBM disease is regarded as a prototypic autoantibody-mediated disease, T cells

clearly have a role in disease induction and persistence, as evidenced by the strong HLA-

association, the presence of affinity-matured and class-switched autoantibody, and the

phenomenon of ‘epitope-spreading’. Indeed, T cells autoreactive to α3(IV)NC1 can be

detected in patients at higher levels than in healthy controls, and their levels wane as disease

resolves50-52. In addition to providing ‘help’ for autoreactive B cells, effector T cells may also

mediate tissue injury in anti-GBM disease. CD4+ and CD8+ T cells can be identified in

glomerular lesions in anti-GBM disease53,54 (though it is not clear that they are antigen

specific) and evidence from experimental animal models suggest that disease can be induced

in the absence of significant humoral immunity55-57. Immunisation with an immunodominant

T cell epitope alone is sufficient to induce both glomerulonephritis and autoantibody

production in mice18, suggesting that injurious T cell responses may incite glomerular

damage, and that the humoral responses required for full disease expression develop as

secondary phenomenon to this initial injury.

It is striking, however, that circulating low level natural autoantibodies to α3(IV)NC1 can be

identified in healthy individuals58. These antibodies have the same epitope specificity as those

found in patients, though IgG2 and IgG4 subclasses predominate. Another study found that

anti-GBM antibodies may be detected in patients several months before the onset of clinical

disease59. In addition, autoreactive T cells can be identified in healthy individuals51. Thus, it is

possible that central immunological tolerance to α3(IV)NC1 is incomplete (despite its

expression in human thymus60) and that autoimmunity to this antigen may lie dormant or

suppressed by regulatory mechanisms in healthy individuals, until an inciting event triggers

disease onset.

One proposed trigger is ‘conformational transition’ of the α3(IV)NC1 autoantigen, within

which two key B cell epitopes have been identified48. In normal circumstances, these epitopes

are cryptic, being buried within the quaternary structure of the NC1 domains. Disruption or

modification of this quaternary structure, perhaps by pulmonary irritants or infection, may

expose these epitopes and allow a fulminant anti-GBM response to develop. A similar

mechanism may also account for the association of anti-GBM disease with other renal

disorders, such as anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV)

and membranous GN61,62, which may likewise disrupt glomerular basement membrane.

Clinical Presentation

The majority of patients present with RPGN (Table 1). That is, a brisk decline in kidney

function in association with glomerular haematuria and proteinuria. RPGN is typically

defined as >50% loss of GFR in less than three months, though in anti-GBM disease the

deterioration can be much more rapid, occurring over a few days or weeks. As such, a short

prodrome of non-specific constitutional symptoms is typical, culminating with overt features

of oliguria, fluid overload and uraemia. Loin pain, attributable to distension of the renal

capsule, and visible haematuria are recognised. Urine microscopy may identify dysmorphic

erythrocytes, and the finding of red blood cells casts is pathognomonic for glomerular

inflammation. Proteinuria is usually in the sub-nephrotic range (<3g/day).

Approximately 40-60% of patients have concurrent alveolar haemorrhage (Table 1), which is

more common in young male patients, and in current smokers28. It may present with cough,

dyspnoea, and haemoptysis, or be apparent radiographically. A disproportionately severe

iron-deficient anaemia should also alert to the possibility of covert underlying alveolar

bleeding. A small proportion of patients (<10%) may present with isolated pulmonary disease

in the absence of renal involvement.

The presence of extra-renal/pulmonary manifestations is uncommon in anti-GBM disease,

and may suggest an alternative cause of pulmonary-renal syndrome, or that the patient has a

co-existing anti-neutrophil cytoplasm antibody (ANCA).

Investigation and Diagnosis

Securing rapid diagnosis in cases of renal-pulmonary syndrome is essential so that directed

therapy can be initiated promptly63. Thus, several imaging and laboratory tests may be

arranged concurrently (Table 2). Central to the diagnosis of anti-GBM disease is the

demonstration of anti-GBM antibodies, either in circulation or in tissue, and confirmation of

glomerulonephritis and/or alveolar haemorrhage.

Detection of Anti-GBM antibodies

In routine clinical practice, circulating antibodies are detected using commercially available

ELISAs or bead-based immunoassays, which are accepted to have high sensitivity and

specificity64. These assays generally use purified or recombinant human or animal GBM

preparations as antigen, and are typically optimised to detect IgG antibodies, thus rare cases

of IgA- or IgM-mediated anti-GBM disease may not be identified65. Alternative methods of

detecting circulating anti-GBM antibodies include Western blot, indirect

immunofluorescence on healthy kidney tissue, or highly sensitive biosensor assay66, though

these methods are generally not available outside of research laboratories. Approximately

10% of patients with anti-GBM disease do not have circulating antibodies detected using

conventional assays, highlighting that over-reliance on serological testing may miss some

cases, and that tissue diagnosis should be obtained where possible.

Direct immunofluorescence for immunoglobulin on frozen renal tissue has high sensitivity

for detecting deposited anti-GBM antibodies. Indeed, renal biopsy may be considered for this

reason in patients presenting with lung haemorrhage but minimal disturbance of renal

function where there is diagnostic uncertainty. Immunoperoxidase techniques using paraffin-

fixed tissue can also be used but may be less sensitive. Other causes of linear deposition of

IgG, such as diabetes and paraproteinemias, should be considered when interpreting

immunohistology. In our experience, direct immunofluorescence of lung tissue in anti-GBM

is prone to false negative results and thus rarely informative.

Renal biopsy findings

Crescentic glomerulonephritis is the hallmark of anti-GBM disease in the kidney21. A

crescent is defined at two or more layers of proliferating cells in Bowman’s space, thought to

arise as a result of severe glomerular inflammation, rupture of the GBM, extravasation of

fibrin and cells into the urinary space, and reactive proliferation of parietal epithelial cells

lining Bowman’s capsule. In anti-GBM disease, crescents are usually widespread, affecting

>50% of glomeruli in 80% of patients8,21, and of similar age and activity (Figure 1), reflecting

abrupt disease onset, and distinguishing it from ANCA-associated vasculitis, where a mix of

cellular, fibrocellular and fibrous crescents are usually observed. Acute tubular injury may be

seen, along with red cell casts in tubular lumens, though interstitial and tubular atrophy are

not prominent unless there is pre-existing renal disease. Vascular lesions are not typical of

anti-GBM disease, unless there is an associated ANCA-mediated process, in which case

necrotizing arteritis or venulitis may be seen in the small and medium sized vessels in the

kidney.

Diagnosis of alveolar haemorrhage

There are no uniform diagnostic criteria for the diagnosis of diffuse alveolar haemorrhage,

and diagnosis is often made on a combination of clinical, radiological and laboratory

findings. This may account for the variable frequency of lung haemorrhage described in

clinical series of anti-GBM disease (Table 1).

Radiology (Figure 2): Plain chest radiography may demonstrate non-specific diffuse

opacification patterns with occasional predilection for the midzones and apical and

costophrenic sparing67. On high-resolution computed tomography, acute alveolar filling with

blood may give ground-glass opacifications, which may progress to frank consolidation,

again with peripheral sparing. As haemorrhage is resorbed in the pulmonary interstitium, later

imaging may show reticular or nodular appearances68.

Broncho-alveolar lavage: Acute alveolar haemorrhage may be indicated by the finding of

haemorrhagic broncho-alveolar lavage fluid, classically with increasing blood content on

successive washes. After 2-3 days, alveolar macrophages convert haemoglobin to

haemosiderin, and these haemosiderin-laden cells may persist in the lung for several weeks,

being evident on Perls staining of broncho-alveolar samples69. Threshold proportions of 20-

30% haemosiderin-laden cells of the total macrophage count have been suggested to be

strongly indicative of diffuse alveolar haemorrhage.

Pulmonary function testing: An increase in diffusing capacity of the lung for carbon

monoxide (KCO) has been reported in alveolar haemorrhage in anti-GBM disease, being

attributed to increased CO uptake by intra-alveolar erythrocytes70. However, this finding may

not be present in all cases71, perhaps due to ventilation-perfusion mismatch in a proportion,

such that measurement of KCO may have useful positive, but not negative, predictive value.

Pathology: Lung biopsy is rarely performed in cases of alveolar haemorrhage in anti-GBM

disease. When undertaken, it is likely to show alveolar lumens filled with erythrocytes and

and haemosiderin-laden cells. Pulmonary capillaritis may be present, with features of

fibrinoid necrosis of capillary walls and inflammation and oedema of the alveolar

interstitium72.

Treatment

Recommended treatment for anti-GBM disease includes plasmapheresis, to rapidly remove

pathogenic autoantibody, along with cyclophosphamide and corticosteroids, to inhibit further

autoantibody production and to reduce tissue inflammation and damage73. Our standard

treatment regimen is summarised in Table 3.

Evidence supporting the use of plasmapheresis in anti-GBM disease comes from

observational studies that indicate improved renal outcomes and patient survival compared to

cohorts treated with immunosuppression alone46,74,75, and one small randomised study that

suggested favourable outcomes and more rapid clearance of anti-GBM antibodies with

plasmapheresis76.

Cyclophosphamide is the most commonly used immunosuppressive treatment in anti-GBM

disease. The majority of reports have used daily oral dosing. The equivalence of pulsed

intravenous therapy for remission-induction in AAV is well-established, though has not been

studied in anti-GBM disease. Of note, a recent nationwide study from France suggests that

patient outcomes may be superior with daily oral dosing, and so this remains our preferred

approach in anti-GBM disease77.

Rituximab has emerged as a useful therapeutic agent in the treatment of many autoimmune

renal diseases. There are approximately 20 case reports of rituximab use in anti-GBM disease

in the literature78, often as an adjunct to conventional therapy. It appears to be associated with

consistent immunological responses, though clinical outcomes are variable. While it may

facilitate more rapid clearance of pathogenic autoantibody, rituximab will have no direct

effects on autoreactive T cells, monocytes, and neutrophils, which experimental models

suggest contribute to disease pathogenesis. There is insufficient evidence to recommend its

use as sole first-line therapy, though it may be considered an alternative where there are

strong contra-indications to the use of cyclophosphamide, or as an adjunct in severe disease.

There are individual case reports of MMF and calcineurin-inhibitor use in the treatment of

anti-GBM disease79-81, though there is likewise insufficient evidence to recommend their

routine use.

In addition to immunosuppression, prophylactic treatments for steroid-induced side effects

and opportunistic infection are recommended, including those for Pneumocystis jiroveci

pneumonia, peptic ulcer disease, oropharyngeal candidiasis, and osteoporosis.

In patients presenting with severe disease, immediate organ support may be required.

Approximately half of patients will have an indication for acute renal replacement therapy at

the time of diagnosis (Table 1). One small series suggests that 11% of patients presenting

with alveolar haemorrhage require artificial ventilation71. In severe lung haemorrhage, extra-

corporeal membrane oxygenation may be considered, and appears to be associated with

favourable outcome despite the requirement for systemic anticoagulation in the setting of

alveolar bleeding (Table 4).

Outcomes

Using the combination of plasmapheresis along with immunosuppressive therapy, the

majority of lung haemorrhage is responsive to treatment. In the largest published series to

consistently employ this approach, 90% of patients with lung haemorrhage had recovery7. A

selected series of alveolar haemorrhage in anti-GBM disease likewise showed high response

rates to treatment, with all patients recovering from pulmonary manifestations71. Data on

long-term respiratory outcomes in anti-GBM disease, however, are scarce. One small study

suggested that patients who had lung haemorrhage have significantly reduced KCO compared

to controls without lung involvement82. However, a subsequent larger series suggested that

long-term respiratory sequalae after lung haemorrhage in anti-GBM disease are not

common71. This is in contrast to AAV, where interstitial lung disease is increasingly

recognised as an important long-term complication, especially in patients positive for MPO-

ANCA, suggesting that distinct mechanisms of pulmonary injury in these dieseases83,84.

Renal responses to treatment are be more variable. Levy et al found that the majority of

patients who do not require immediate renal replacement therapy (RRT) had a favourable

renal outcome, with 95% and 91% renal survival at 1 and 5 years, respectively, in those with

a presenting serum creatinine of <500umol/L7. In those presenting with creatinine

>500umol/L (but not requiring RRT), the corresponding renal survival rates were 82% and

50%, respectively. In those presenting with an immediate need for RRT, however, long term

renal survival was poor. Several series suggest that fewer than 10% of cases will recover

independent renal function, with only 8% renal survival at 1 year in the Hammersmith series

(Table 1).

Several studies have aimed to identify reliable predictors of renal outcome. Severity of renal

dysfunction at presentation, the proportion of glomeruli affected by crescents, and

oligoanuria at presentation, have each been associated with renal outcome7,21,85. A recent

worldwide, multi-centre study recruited 123 cases with renal-biopsy proven anti-GBM

glomerulonephritis, with median follow up of 3.9 years, making it the largest

histopathological study in anti-GBM disease to date86. It confirmed previous observations of

most favourable outcomes in patients presenting with creatinine of <500µmol/L. Independent

predictors of ESRD were dialysis-requirement at presentation, reduced proportion of normal

glomeruli, and increased interstitial infiltrate on kidney biopsy. Of note, no patient with 100%

crescents or >50% sclerotic glomeruli recovered renal function.

Anti-GBM disease is usually a ‘one-hit’ phenomenon, and relapses are rare. Even in the

absence of immunosuppression, there is a progressive fall in autoantibody titres and numbers

of autoreactive T cells, accompanied by the development of a CD25+ suppressor T cell

subset, suggesting that immunological tolerance to α3(IV)NC1 is reinstated87. When relapses

do occur, it is often in association with ongoing exposure to pulmonary irritants, and their

avoidance once identified is essential for long-term management.

Transplantation in Anti-GBM Disease

Renal transplantation should not be performed in the presence of circulating anti-GBM

antibodies, as there is a high risk of disease recurrence47. Most centres therefore recommend a

six month period of sustained negative testing for anti-GBM antibodies before undertaking

transplantation surgery. With these conditions, recurrent disease in renal allografts is rare,

and patient and allograft survival are at least comparable to, if not better than, those

transplanted for other causes of ESRD9,88.

Diffuse alveolar haemorrhage is generally responsive to treatment, and not associated with

long-term pulmonary complications. As such, we are aware of only one case of anti-GBM

disease requiring lung transplantation, which had good long-term outcome89.

Isolated Pulmonary Involvement in Anti-GBM Disease

Presentation with isolated or predominant pulmonary involvement in anti-GBM disease is

recognised, though uncommon, being estimated to occur in <10% of patients in larger series.

Such cases are not extensively characterised, perhaps reflecting publication bias from renal

centres, though there are small case series90,91. Some patients may have mild urinary

abnormalities and minor proliferative changes on renal biopsy, but with preserved excretory

renal function, while others may have no clinical or histological evidence of renal of renal

inflammation. Renal biopsy, however, may still reveal linear deposits of immunoglobulin,

including in those patients who are negative by serological assay. A small series from

Sweden recently described four young female patients who presented with severe alveolar

haemorrhage and favourable renal outcome, who were seronegative for circulating anti-GBM

antibodies by conventional assay92. They were, however, found to have circulating IgG4 anti-

GBM antibodies by dedicated ELISA, and confirmed on kidney biopsy. Together, these

findings suggest that clinical presentation in anti-GBM disease may be influenced by

differences in antibody subclass or antigen target, and also highlight the need to consider

variant anti-GBM disease in cases of ‘idiopathic’ pulmonary haemorrhage.

‘Double positive’ ANCA and Anti-GBM Disease

A significant proportion of patients with anti-GBM disease will also have detectable ANCA

in circulation, occurring in 20-40% of cases in larger series (Table 1). Conversely, one study

suggested that up to 5% of patients with ANCA have detectable anti-GBM antibodies93. This

incidence of ‘double positivity’ occurs at much higher rates that would be expected by chance

alone, though the mechanism of association is not understood. It appears that double positive

patients initially present with the severe disease manifestations of anti-GBM disease, with

high rates of severe renal failure and diffuse alveolar haemorrhage requiring intensive

treatment with plasmapheresis and immunosuppression. During long-term follow-up,

however, they demonstrate a tendency to relapse at the frequency of patients with AAV, and

thus they require long-term maintenance immunosuppression, unlike patients with isolated

anti-GBM disease61.

Conclusions

Anti-GBM disease is rare disorder, though an important differential in patients presenting

with RPGN, pulmonary haemorrhage, or a combined renal-pulmonary syndrome. The clinical

features may be non-specific, thus a high-index of suspicion is required. Rapid serological

testing may facilitate early diagnosis, though a proportion of patients are negative for

circulating antibodies, including those presenting with predominant pulmonary involvement.

In these cases, renal biopsy may identify deposited anti-GBM antibody, with or without

evidence of glomerulonephritis, and allow prompt initiation of directed treatment with

plasmapheresis and immunosuppression, that may successfully treat life-threatening alveolar

haemorrhage and prevent long-term renal failure.

Tables and Figures

Table 1: Clinical studies in anti-GBM disease (including studies describing >40 patients, reported after 1990)

Study, Publication

yearCases (n)

ANCA Double-

Positive (%)

RRT at Diagnosis

(%)

Alveolar Haemorrhag

e (%)

Patient survival %

Renal survival %

van Daalen, 201786

123 32% 56% 35% 83% at 5 years

34% at 5 years

McAdoo, 201761 78 47% 60% 38% 86% at 1

year49% at 1

yearHuart, 201677 122 15% 68% 77% 86% at 1

year38% at 1

yearAlchi, 201585 43 21% 81% 40% 88% at 1

year16% at 1

year

Cui, 201175 176 22% N/A 46% 73% at 1 year

25% at 1 year

Hirayama, 200894 47 13% 60% 23% 77% at 6

months21% at 6 months

Segelmark, 200343 79 37% 46% 23% 64% at 6

months20% at 6 months

Levy, 20017 71 Excluded 55% 62% 77% at 1

year53% at 1

yearDaly,

199695 40 N/A 50% 67% 94% at last FU

24% at last FU

Abbreviations: RRT, renal replacement therapy; PEX, plasma exchange; CYC, cyclophosphamide; CS, corticosteroids; ESRD, end stage renal disease; FU, follow up.

Table 2: Differential diagnosis and investigation of immunological reno-pulmonary syndromesDifferential Diagnoses Serological tests

ANCA-associated vasculitis

Granulomatosis with polyangiitis

ANCA IIF ANCA ELISA ANA, ENA ds-DNA Ab C3, C4 Immunoglobulins Rheumatoid Factor Cryoglobulins Lupus anticoagulant Anti-phospholipid Ab Haemolytic assessment

including Blood film

Microscopic polyangiitis

Eosinophilic granulomatosis with polyangiitis

Immune-complex small vessel vasculitis

Systemic lupus erythematosus

Cryoglobulinaemic vasculitis

Henoch Schonlein purpura/IgA vasculitis

Mixed connective tissue disease

Systemic sclerosis

Dermato/polymyositis

Antiphospholipid syndromes With vasculitis or with pulmonary embolism

Abbreviations: ANCA, anti-neutrophil cytoplasm antibody; IIF, indirect immunofluorescence; ELISA, enzyme linked immunosorbent assay; ANA, anti-nuclear antibody; ENA, extractable nuclear antigen antibody; ds-DNA, double-stranded DNA.

Table 3: Initial Treatment of Anti-GBM Disease (Modified from Reference96)Agent Details

Plasmapheresis

Daily 60ml/kg (max 4L) exchange for 5% human albumin solution. Add fresh human plasma (300-600 mL) within 3 days of invasive procedure

(e.g., kidney biopsy) or in patients with alveolar haemorrhage. Continue until antibody levels are fully suppressed. Monitor antibody levels

regularly after cessation of treatment as plasma exchange may require reinstatement if antibody levels rebound.

Monitor and correct as required: platelet count, aim > 70 × 109/L; fibrinogen, aim > 1 g/L (may require cryoprecipitate supplementation; haemoglobin, aim for > 90 g/L; corrected calcium, aim to keep in normal range

Cyclophosphamide

2 mg/kg/day given orally for 2–3 months. Stop if leukocyte count falls to < 4 × 109/L and restart at reduced dose when

recovered. Insufficient evidence to recommend use of IV cyclophosphamide.

Corticosteroids

Prednisolone 1 mg/kg/day (maximum 60 mg) given orally. Reduce dose weekly to 20mg by 6 weeks, then gradually taper until complete

discontinuation at 6–9 mo. There is no evidence to support the use of methylprednisolone, and it may

increase the risk of infectionAbbreviations: GBM = glomerular basement membrane; IV = intravenous. Table adapted from references.

Table 4: Reported cases of extra-corporeal membrane oxygenation in anti-GBM disease

Publication Case Details Duration of ECMO Anticoagulation Other

Treatments Outcome

Balke, 201597

29FDAH only 7 days UFH

Target PTT 70s

PEXCYC

Steroids

Extubation day 12.Discharge day 30.No radiographic evidence of residual lung disease

Herbert, 201498

16FDAH & RPGN 26 days No

anticoagulation

PEXCYCIVIG

Steroids

Temporary tracheostomy day 33.Discharge day 68.Regained independent renal function.

Dalabih, 201299

9FDAH & RPGN 6 days

UFHTarget ACT 200-

220s

PEXCYC

Steroids

Extubation day 14.Discharge day 47.Lung function testing suggests no residual disease.ESRD requiring peritoneal dialysis.

Legras, 201589

20MDAH only

121 days Not givenPEXCYC

Steroids

Double-lung transplantation day 121.Extubation week 3 post-op.Discharge week 5 post-op.Well 20 months post-op.

De Rosa, 201533

20MDAH only 9 days Not given

PEXCYCIVIG

Steroids

Discharge day 20.

Daimon, 1994100

49MDAH & RPGN 3 days

Nafamostat mesilate

Target ACT 150s

PEXSteroids Death from respiratory failure day 4.

Abbreviations: DAH, diffuse alveolar haemorrhage; RPGN, rapidly progressive glomerulonephritis; UFH, unfractionated heparin; PEX, plasmapheresis; CYC, cyclophosphamide, IVIG, intravenous immunoglobulin; partial thromboplastin time; ACT, activated clotting time; ESRD, end-stage renal disease

Figure 1: Crescentic glomerulonephritis: Renal biopsy demonstrating synchronous, large circumferential crescent formation in adjacent glomeruli.

Figure 2: Radiographic findings in diffuse alveolar haemorrhage in anti-GBM disease. Left panel, emergency plain chest rardiograph demonstrating widespread bilateral airspace consolidation. Right panel, high resolution CT demonstrating occult patchy ground-glass opacifications in both hemithoraces, with subpleural sparing.

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